(Corbin) Dry Eye

1

Diagnosis and Clinical Management of

Dry Eye SyndromeCOPE Course 19153 AS

Diagnosis and Clinical Management of

Dry Eye SyndromeCOPE Course 19153 AS

[email protected]

COPE Course 19153-ASCOPE Course 19153-AS

Glenn S. Corbin, ODPrivate Practice, Reading, PAAdjunct Faculty, PCO at Salus University

Disclosure

I am a consultant for Alcon Laboratories, Inc. I have no financial interest in any Alcon

d t A ti f ff l b l/products. Any mention of an off-label/non-FDA approved use of any drug or product is strictly the opinion of the speaker, not of the Course Administrator.

Objectives

Discuss the prevalence as well as related structures and systems associated with dry eye

Describe the global features of dry eye Discuss current diagnostic practicesDiscuss current diagnostic practices Discuss and compare current therapeutic

management options Review results of relevant pre-clinical and

clinical trials Review pharmaceutical treatments under

investigation

The Tear Film is the Most Important Refracting Surface of the Eye

Ocular Surface Disease andAdvanced Technology

Quality of vision starts with a healthy tear film.

All of the recent advances in cataract and refractive technology are lost with even minimal compromise of the ocular surface.

Minimal Disruption of the Ocular Surface Can Severely Degrade Visual Acuity

2

Changing ParadigmsDEWS 1995

1Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eye CLAO J, 1995, 21:221-32.

Changing ParadigmsDEWS 2007

2Lemp MA, Baudouin C, Baum J, et al. The definition and classification of dry eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop (2007). Ocular Surface 2007;5:75-92.

Clinically speaking,you may be doing it wrong if you

Diagnose and treat dry eye at the routine general vision exam visit

Dont schedule an OSD assessment visit prior to treatment

Dont prescribe a specific treatment regimen and dosing schedule and just offer a grab bag approach

Dont routinely schedule a follow up visit to assess your patients progress with your treatment

Dont manage dry eye as seriously as other chronic diseases

Do your patients ever complain of Blurry vision: constant or intermittent Burning Tearing Foreign body sensation

Itching Itching Tired eyes Sore eyes Sensitive eyes Photophobia Dry eyes My eyes just dont feel right

They May Have Dry Eye

Probably the most common presentation to an eye care practice and an often missed diagnosis or mis-diagnosed ophthalmic disease

Represents an untapped opportunity to p pp pp yimprove your patients ocular and visual comfort

Represents a potential goldmine to increase practice growth and profits through medical eye care services

And now, the rest of the story.

Ocular Surface Disease is Markedly Under-Diagnosed

39.00 55.55

30

45

60

ns o

f Peo

ple

ns o

f Peo

ple

There are an There are an estimated estimated 55 55 million Americans million Americans with dry eye with dry eye disease. Most of disease. Most of them are elderly.them are elderly.

3939

1Mattson Jack Epidemiology Analysis. 20052The 2004 Gallup Study of Dry Eye Sufferers. 2004.

16.55

0

15

ECP-Diagnosed Dry

Eye

UndiagnosedDry Eye

Total Dry EyePatient

Population12

2

Mill

ion

Mill

ion

An An estimated 39 estimated 39 million dry eye million dry eye sufferers may not sufferers may not have been have been diagnosed diagnosed by an by an eye care eye care professional.professional.

3

Dry Eye Difficult disease to understand and treat

Varied causes and severities

Can be a stand-alone condition

More common in older individuals (45 years or older)More common in older individuals (45 years or older)

Affects women more commonly than men

Functional visual acuity may be significantly decreased

Quality of life impact similar to moderate-severe angina

Schiffman RM, Walt JG, Jacobsen G, Doyle, et al, Utility assessment among patients with dry eye disease. Ophthalmology, 2003;110(7): 1412-1419

Prevalence of Dry Eye Disease

Study N Age Criteria Prevalence ReferenceWisconsin 3,722 48-91 Self-reported 14.4% Moss et al,

2000

Melbourne 926 40 97 2 or more signs 7 4% McCarty et alMelbourne 926 40-97 2 or more signs 7.4% McCarty et al, 1998

Maryland 2,520 65-84 Symptoms + 1 sign 3.5% Schein et al, 1997

Womens health

39,876 49-84 (female)

Severe symptoms or clinical diagnosis

7.8% Schaumberg et al, 2003

Schaumberg et al. Am J Ophthalmol. 2003;136:318

age adjusted > 3.2m women

How Does Dry Eye Impact or Affect Patient QOL?

In a survey of 100 patients with dry eye Patients reported that they suffered from

dry eye for a median 48 months (mean 86.8dry eye for a median 48 months (mean 86.8 months, SD 103.9 months)

Most patients (75.8%) felt that their dry eye had worsened over time

Data on file, Allergan

How Does Dry EyeAffect Your Reading?

33.3354045

ient

s

AlotSomewhatA Little

44.4

Data on file, Allergan

13.18.1

05

1015202530

Perc

enta

ge o

f Pat Not at All

Computer Use 32.3 26.3 11.1 8.1 0.0

ADL 47.5 35.4 13.1 3.0 1.0

Never

Signs vs. Symptoms one study found that 3 patients with moderate to severe

symptoms had NO surface staining another study found lack-luster repeatability in most dry eye

measurements (corneal staining and MGD scores)This study found that low (< 10mm) Schirmer scores (more advanced disease) showed better repeatability and TBUT repeatability was substantialp y

both investigator groups found high repeatability of subjective reporting of symptomsAdditionally, these investigators found that patients typically perceive their dry eye to be worse than what the doctor perceives (4x more likely)

one study reports dry eye patients have more psychological problems and disturbances, such as emotional instability and depression

Aqueous DeficiencyNeurologicalPemphigoid

L p s

Underlying Causes of Dry Eye Disease

Lipid Deficiency Mucin Deficiency

SjogrensInflammation

Ocular Surface Disease

LupusStevens-Johnson

CombinationDeficiencies

4

Influential Factors of Dry Eye

Adverse Conditions

Arid Conditions(e.g. Midwest)

Windy Environments(e.g. air conditioning,

forced heat)

Pollutants(e.g. exhaust, smoke, smog)


Adverse Conditions

Visual Tasking (e.g. PC use)

Systemic Medications (e.g. anti-histamines)

Foods / Drink (e.g. alcohol)


Age Gender Osteoporosis Gout Ocular surgery Contact lens wear Nutritional problems Rh t id th iti

LASIK surgery Cosmetic surgery Exposure keratitis Entropion Ectropion Symblepharon Lid notches L hth l

Temperature Humidity Air movement Allergies Reading/CRT Watching movies Sleep Ill i ti Rheumatoid arthritis

Thyroid disease Time of day

Lagophthalmos Incomplete blinking Dellen formation Conjunctivochalasis

Illumination Medications Topical medication

preservatives

Prause JU, Norn M. Relation Between Blink Frequency and Break-Up Time. Acta Ophthalmol. 1983 61: 108-116.Cho P, Cheung P, Leung K, Ma V, Lee V. Effect of Reading on Non-Invasive Tear Break-Up Time and Inter-Blink Interval. Clin. Exp. Optom. 1997 80: 62-8.Tsubota K, Seiichiro H, Okusawa Y, Egami F, Ohtsuki T, Nakamori K. Quantitative Videographic Analysis of Blinking in Normal Subjects and Patients with Dry Eye. Arch. Ophthalmol. 1996 114(6): 715-720.Nally L, Ousler GW, Abelson MB. Ocular discomfort and tear film break-up time in dry eye patients: a correlation. IOVS 2000 41(4): 1436. Collins M, Seeto R, Campbell L, Ross M. Blinking and Corneal Sensitivity. Acta Ophthalmologica 1989 67(5): 525-531.Abelson MB, Holly FJ. A tentative mechanism for inferior punctate keratopathy. Am. J. Ophthalmol. 1977 83: 866-869.Doane MG. Dynamics of the Human Blink. Ber. Disch. Ophthalmol. Ges. 1980 77: 13-17.Kaneko K, Sakamoto K. Spontaneous Blinks as a Criterion of Visual Fatigue During Prolonged Work on Visual Display Terminals. Perceptual and Motor Skills 2001 92(1): 234-250.

-Adrenergic-blocking, Anti-anginals and Anti-hypertensives(e.g. Atenolol, Metoprolol)

Alkylating Immunosuppressives(e.g. Busulfan, Cyclophosphamide)

Influential Factors of Dry Eye Common Classes of Drying Systemic Medications

Tricyclic Anti-depressants(e.g. Amitriptyline, Doxepin)

Oral Anti-histamines(e.g. Loratadine, Clemastine, Hydroxyzine)

Cyclophosphamide)

Diuretics(e.g. Triamterene, Hydrodiuril)

Estrogen

Drying Systemic MedsClinical Study Protocol

To investigate the ocular drying effect of a commonly prescribed oral antihistamine (loratadine/Claritin) in normal subjects when exposed to a controlled adverse

Study Rationale

subjects when exposed to a controlled adverse environment (CAE) for 45 minutes

To examine a possible dose effect between QD and BID treatment with loratadine, 10 mg.

Welch, Ousler, Abelson. Ocular drying associated with oral antihistamines (Loratadine) in the normalpopulation. Cornea 2000 19: (Suppl): S135.

Keratitis Conjunctival Staining

2.3

3.0

2

2.5

3

3.5

4

itis

(0 -

4)

3.9

2.422.5

3

3.5

4

al S

tain

ing

(0 -

4)

Drying Systemic MedsClinical Study RESULTS

QD = 81% increase (1 unit)BID = 130% increase (1.7 units)

QD = 71% increase (1 unit)BID = 175% increase (2.5 units)

1.3

0

0.5

1

1.5

Untreated QD; 4 Days BID; 4 Days

Ker

at

1.4

0

0.5

1

1.5


Con

junc

tiva

5

TFBUT Ocular Discomfort

3 2

5.4

3

4

5

6

me

(sec

.)

2

3

4

Ocula

r D

iscom

fort

(0 -

4)

UntreatedClaritin (QD 4 days)

Drying Systemic MedsClinical Study RESULTS

QD = 41% decrease (2.2 sec)BID = 67% decrease (3.6 sec)

QD and BID increased at all but one time point (10 min. QD)

1.8

3.2

0

1

2


Tim

0

1

0 5 10 15 30 45

CAE Exposure Time (min.)

Claritin (QD, 4 days)Claritin (BID, 4 days)

Drying Systemic Meds: Clinical StudyDrying Systemic Meds: Clinical StudyTear Flow and Volume ResultsTear Flow and Volume Results

It has been shown that loratadine 10 mg causes clinically meaningful damage to the ocular surface due to its anti-muscarinic action (M3)1

Both tear flow and volume are decreased as a result of 4-day dosing with loratadine, as measured by fluorophotometry

1 Welch, Ousler, Abelson. Ocular drying associated with oral antihistamines (Loratadine) in the normalpopulation. Cornea 2000 19: (Suppl): S135.

Benzalkonium ChloridePreservative Effect

Short term effects* Can accelerate break up of the tear film Can cause transient corneal epitheliopathy

Long term effects* Effects are dose-dependent and can range

from apoptosis to necrosis Local inflammation causes changes that

can mimic the signs & symptoms of dry eye

*Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther. 2001;18:205-215.

When May BAK Use Be Most Problematic?

G th A t N iA i0.0001% BAK 0.050.1% BAK0.01% BAK Growth Arrest NecrosisApoptosis

1. Noecker R. Rev Ophthalmol. 2001(6).

Concentration and Duration determine the Dose

Is Long Term BAK Use a Big Deal? The Single Most Critical Advance in

The Treatment of Dry Eye Came With The Elimination of Preservatives, Such as BAK From OTC Lubricants1

BAK is Largely Responsible for The Ocular Toxicities and Inflammation Associated With The Chronic Use of Many Ophthalmic Solutions2

1. Pflugfelder SC, et al. Management and therapy of dry eye disease: Report of the management and therapy subcommittee of the international dry eye workshop (2007). The Ocular Surface. 2007;5:163-178.

2. Baudouin C, Riancho L. In vitro Studies of antiglaucomatous prostaglandin analogues: travoprost with and without benzalkonium chloride and preserved latanoprost. Investigative Ophthalmology & Visual Science. 2007;48:41234128.

BAK Reduces Tear Film Break Up Time (TBUT) in 30 Healthy Volunteers

A randomized double - blind crossover study with instillation of one drop in each eye followed by a 5 day washout then the other drop instilled

TBUT (Seconds)TBUT (Seconds) CARTEOLOLCARTEOLOLWITHOUT BAKWITHOUT BAKCARTEOLOLCARTEOLOLWITH BAKWITH BAK

Baseline Baseline 9.09.0 10.4 10.4

30 minutes later30 minutes later 8.1 8.1 7.9 7.9

* Decrease in Tear Film Break Up Time at 3 hours from baseline was significantly lower in the BAK- free group than in the preserved carteolol (p=0.04)

Significantly lowered compared with baseline (p=0.001)

Baudouin C, de Lunardo C. Short term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers. Br J Ophthalmol. 1998;82:39-42.

1 hour later1 hour later 7.3 7.3 7.4 7.4

3 hours later*3 hours later* 7.9 7.9 6.16.1

Decrease from Baseline at 3 hours -1.1 -4.3

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Tear Film Physiology

Mucin layer (hydrophilic coating) extends in a gradient throughout the aqueous Secreted by goblet cellsy g

Aqueous layer (transports principle tear components) Secreted by primary and

accessory lacrimal glands Lipid layer (limits tear

evaporation) Secreted by meibomian

glands

Normal Ocular Surface and Epithelial Glycocalyx

Lipids

Aqueous with

The glycocalyx is produced by corneal epithelial surface cells. It functions to help bind mucins and tears onto the

corneal surface.

Surface cell microvilli

Aqueous with soluble mucins

Corneal epithelial cells

Secretomotor N I l

The Healthy EyeHomeostasis

Normal tearingNormal tearingdepends on adepends on a

neuronal feedback neuronal feedback looploop

LacrimalGlands

Nerve Impulses

Tears Support and MaintainOcular Surface

Ocular SurfaceNeural Stimulation

Stern et al. Cornea. 1998:17:584

Components of Healthy Tears

A complex mixture of proteins, mucins, and electrolytes

Antimicrobial proteins:lysozyme, lactoferrinG th f t d Growth factors and suppressors of inflammation

Membrane-bound mucins 1, 4 and soluble 5AC

Electrolytes for proper osmolarity

Image from Dry Eye and Ocular Surface Disorders, 2004

Lacrimal Glands:Lacrimal Glands: Chronic IrritationChronic Irritation TT--cell activationcell activation Cytokine secretion into Cytokine secretion into

Interrupted Secretomotor Interrupted Secretomotor Nerve ImpulsesNerve Impulses

Disruption ofDisruption ofnormal neuronalnormal neuronalcontrol of tearingcontrol of tearing

Dry Eye Disease

yytearstears

Nerve ImpulsesNerve Impulses

Tears Damage Ocular SurfaceTears Damage Ocular Surface

Cytokines Cytokines Disrupt Neural ArcDisrupt Neural Arc

Stern et al. Cornea. 1998:17:584

inflammation

Dry Eye:Dysfunction of the Neural Loop?

Normal function of neural loop Should respond to restore any deficit of the tear film

Apparent dysfunction in dry eye: Decreased secretory response to stimulus Due to effects of ocular surface pathology on corneal nerves?

Increased tear osmolarity, tissue damage Or due to damage/loss of tear-secreting glands?

Stern et al, 1998

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Tears in Chronic Dry Eye (CDE)differ from Normal tears

Lesser concentrations of many proteins in CDE e.g. antimicrobial proteinsLactoferrin levels lower in dry eyepatients as compared to controls

Epidermal growth factor concentrations decreasedC t ki b l hift d Cytokine balance shifted, promotes inflammation

Soluble mucin 5AC greatly decreased Due to loss of goblet cells Impacts viscosity of tear film

Activated proteases Degrade extracellular matrix and

tight junctions Increased electrolytes

Ohashi et al. Am J Ophthalmol. 2003;136:291

Unhealthy tears in dry eye causesquamous metaplasia and loss of goblet cells.

.which decreases soluble mucins, worsening unhealthy tears

Normal conjunctival epithelium, goblet cells are violet.

Squamous metaplasia withloss of goblet cells.

Images from Dry Eye and Ocular Surface Disorders, 2004(Kunert et al, 2002; Zhao et al, 2001)

What Happens During LASIK?

Shamik Bafna and Roger F. Steinert. In Albert, Jakobiec (Eds). 2000. WB Saunders

Total number of sub-basal and superficial stromal nerves is decreased by 90% after LASIK surgery1

1. Lee et al. IOVS 2002.

Effect of Denervation

Healthy Ocular Surface

LASIK

Denervation of Ocular Surface

CornealSensitivity

Blink Rate

Aqueous(Reflex Tearing)

Inter-Blink Interval

Mucin

LipidUnhealthy Ocular Surface

Symptoms

Keratitis

ConjunctivalStaining

TFBUT

VulnerabilityMitosis

Corneal Sensitivity and Blink Rate in Normals and Dry Eye Patients

/ Min

ute

rate

Normals withNormal Corneal

Sensitivity

Dry Eye withNormal Corneal

Sensitivity

Blin

ks /

Dry Eye withLow Corneal

Sensitivity

N = 8 N = 9 N = 12

Nally, Ousler, Abelson. (Abstract). ARVO 2003

rate

LASIK Associated Dry Eye: Clinical Study

Title:

Effects of LASIK on Tear Production, Clearance and the Ocular Surface

Methods:Methods:

48 eyes underwent LASIK

Evaluations: tear fluorescein clearance, staining, tear production (Schirmers), and corneal / conj. sensitivity at baseline, 7 days and 1, 2, 6, 12 and 16 months after LASIK.

Battat L, Macri A, Bursun D, Pflugfelder S. Ophthalmol 2001108:1230-1235.

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Results:

Corneal and conj. sensitivity decreased at 1 week, and 1, 12, 16 months (p < 0.007 at all visits)

Schirmers decreased from 24mm (pre op) to 18mm (1

LASIK Associated Dry Eye: RESULTSClinical Study

Schirmer s decreased from 24mm (pre-op) to 18mm (1 month post-op) (p

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Patient EducationBefore the diagnostic evaluation.

At the end of the routine exam, explain the tentative diagnosis (of a possible tear film abnormality) to your patient and that you will need to perform specific tests to confirm the diagnosis

Always explain that the testing is medical, not vision y p gcare, and is usually covered by most health insurance plans

After the diagnosis. After making the diagnosis, be specific about the

treatment that you prescribe and prognosis Follow up on the therapy that is prescribed to assess

efficacy

OCULAR SURFACE DISEASE INDEXPlease Answer The Following Questions by Checking The Box That Best Represents Your Answer

OCULAR SURFACE DISEASE INDEXPlease Answer The Following Questions by Checking The Box That Best Represents Your Answer

All of the time Most of the time Half of the time Some of the time None of the time

1 Eyes that are sensitive to light? 4 3 2 1 0

2 Eyes that feel gritty?

3 Painful or sore eyes?

4 Blurred vision?

5 Poor vision?

Have problems with your eyes limited you in performing any of the following during the last week:Have problems with your eyes limited you in performing any of the following during the last week:All of the time Most of the time Half of the time Some of the time None N/A

Have you experienced any of the following during the last week:Have you experienced any of the following during the last week:

6 Reading?

7 Driving at night?

8 Working with a computer or bank machine (ATM)?

9 Watching TV?

Have your eyes felt uncomfortable in any of the following situations during the last week:Have your eyes felt uncomfortable in any of the following situations during the last week:All of the time Most of the time Half of the time Some of the time None N/A

10 Windy conditions?

11 Placed or areas with low humidity (very dry)?

12 Areas that are air conditioned?

OSDI Severity GradingOSDI Severity Grading

Severe

0 10 20 30 40 50 60 70 80 90 100Score

0-12 23-3213-220 33-100

Total OSDI Score=(Sum of Score for All Questions Answered) X (25)

(Total # of Questions Answered)

Mild ModerateNormal SevereScore

Miller KL, Mink DR, Mathias SD, & Walt JG. Estimating the minimal clinical important difference of the Ocular Surface Disease Index: Preliminary findings [Abstract]. Abstract obtained from www.isoqol.org/2006AbstractsBook.pdf.

OSD Exam FormOSD Exam FormDate:___/___/____ Patient _________________________________________________History/CC:_______________________________________________________________________________________________________________________________________________________________________________________________________________________Risk Factors: meds ( ) systemic disease ( ) environment ( ) CL wear ( ) Other ( )Visual Acuity: cc / sc O.D. 20/ O.S. 20/

O.D. O.S. External Exam:

Rosacea Y / NComplete Blink Y / N Y / NLagophthalmus Y / N Y / NScleral Show Y / N Y / NNotches Y / N Y / NEctropion Y / N Y / NEntropion Y / N Y / N

OSD Exam FormOSD Exam Form

Biomicroscopy:

Anterior Blepharitis Y / N Y / NPosterior Blepharitis Y / N Y / NC j ti h l i Y / N Y / NConjunctivochalasis Y / N Y / NEBMD Y / N Y / NTFBUT < 5 sec / > 5 sec < 5 sec / > 5 secTear Meniscus scant / normal scant / normalDebris/Frothing Y / N Y / NLid Wiper Epitheliopathy Y / N Y / NNaFl Staining Y / N Y / NLissamine Green Y / N Y / NSchirmer I / II ____mm ____mmZone Quick ____mm ____mmExternal Photos Y / NTopography Y / N

OSD Exam FormOSD Exam Form

Diagnosis: _____________( )_______________( ) ( ) ( )

Initial Treatment:Pt. Education: Lid Hygiene:OTC meds: Rx meds:Nutritional Supplements:Punctal Occlusion: Collagen 7 Day/ 90 Day SmartPlug/Silicone RU / RL / LU / LL

Additional notes:

RTO:______________________O.D.

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Dry Eye History: Symptoms

Take a comprehensive detailed history and be sure to listen carefully t ll ti t t A kto all patient symptoms. Assess work and home environment

Be sure to differentiate refractive symptoms from possible ocular surface disease symptoms

Diagnostic Procedures

Lid Evaluation: perform a thorough external exam

Biomicroscopic Evaluation of the eyelids, puncta corneas and conjunctivaepuncta, corneas and conjunctivae lagophthalmus, notches, entropion,

ectropion, lid laxity, blink rate, incomplete blinking, conjunctivochalasis, anterior blepharitis, MGD (and associated signs), lesions, epitheliopathies (EBMD), etc.

Eyelid PathologyEyelid Pathology Diagnostic ProceduresDiagnostic Procedures

Lid EvaluationLid Evaluation: perform a thorough external : perform a thorough external examexam

BiomicroscopicBiomicroscopic EvaluationEvaluation of the eyelids, of the eyelids, punctapuncta corneas and conjunctivaecorneas and conjunctivaepunctapuncta, corneas and conjunctivae, corneas and conjunctivae lagophthalmuslagophthalmus, notches, , notches, entropionentropion, ,

ectropionectropion, lid laxity, blink rate, incomplete , lid laxity, blink rate, incomplete blinking, blinking, conjunctivochalasisconjunctivochalasis, anterior , anterior blepharitisblepharitis, MGD (and associated signs), , MGD (and associated signs), lesions, lesions, epitheliopathiesepitheliopathies (EBMD),(EBMD), etc.etc.

ConjunctivochalasisConjunctivochalasis((CChCCh))

Caused by poor adhesion between Tenons capsule and the sclera

CCh

11

Two primary formsAnterior blepharitis Inflammatory condition of the exterior eyelids Often secondary to infection or associated with acne

rosacea or seborrheic dermatitis of the scalp or facial areas

Posterior blepharitis: Meibomian gland disease (MGD) Inflammation of the interior eyelids

Blepharitis A Common Ocular DisorderBlepharitis A Common Ocular Disorder

Anterior blepharitis

61

Inflammation of the interior eyelids Associated with altered composition of the

meibomian gland secretions & inflammation

Meibomian gland disease

Spectrum of Spectrum of BlepharitisBlepharitis

MixedMixedAnterior Anterior blepharitisblepharitisPosteriorPosteriorblepharitisblepharitis

Anterior BlepharitisAnterior BlepharitisAnterior BlepharitisAnterior Blepharitis

Inflammation of the outside of the eyelids Inflammation of the outside of the eyelids usually caused by bacterial infection usually caused by bacterial infection (staphylococcal) of the eyelid margin(staphylococcal) of the eyelid margin Infection normally occurs at the origins of Infection normally occurs at the origins of

the eyelashes and involves the lash the eyelashes and involves the lash follicles and the follicles and the meibomianmeibomian glandsglands

62

follicles and the follicles and the meibomianmeibomian glandsglands Signs and symptoms include:Signs and symptoms include: Morning crusting of lidsMorning crusting of lids CollarettesCollarettes -- scales that encircle lashscales that encircle lash Loss of lashesLoss of lashes Lid margin rednessLid margin redness ConjunctivalConjunctival hyperemiahyperemia

Meibomian Glands Important For Ocular Surface HealthMeibomian Glands Important For Ocular Surface Health

Enlarged sebaceous glands located posterior to eyelashes

Produce lipids and deliver them to the ocular surface where they serve as the outer layer of the tear film Stabilizes the tear film

63

Retards evaporation Helps maintain a smooth,

homogeneous refractive surface Provides a barrier to contamination

and damage to the eye

The maintenance of a free-flowing liquid lipid secretion is essential for maintaining a stable tear film

Meibomian Gland Disease EtiologyMeibomian Gland Disease Etiology

Meibomian gland disease involves a change in composition of meibomian gland secretions that leads to inflammation, irritation and an altered tear film Normal Normal meibomianmeibomian gland secretions convert from unsaturated gland secretions convert from unsaturated

lipids (that melt at body temperature) to saturated fatslipids (that melt at body temperature) to saturated fats

64

Involves degradation of triglycerides to mono- and diglycerides(solid), leading to MG obstruction Lipases appear to be involved in the degradation

The mono- and diglycerides are pro-inflammatory, leading to the inflammation and irritation associated with MGD

Posterior Blepharitis (Meibomian Gland Disease) Posterior Blepharitis (Meibomian Gland Disease)

Signs and symptoms include: Signs and symptoms include: Dilated & plugged Dilated & plugged meibomianmeibomian

gland orifices with toothpaste gland orifices with toothpaste like materiallike materialThi k d lid iThi k d lid i

65

Thickened lid marginThickened lid marginFilmy vision with foam in tear Filmy vision with foam in tear

film (soaps/fatty acids)film (soaps/fatty acids)Dry eye signs and symptoms Dry eye signs and symptoms

(burning, foreign body sensation, (burning, foreign body sensation, contact lens intolerance)contact lens intolerance)

Why is it important to treat Why is it important to treat Blepharitis?Blepharitis?

Why is it important to treat Why is it important to treat Blepharitis?Blepharitis?

12

Why Is It Important to Treat Anterior Blepharitis?Why Is It Important to Treat Anterior Blepharitis?

To prevent conjunctival hyperemia (red eyes) which can be a significant problem for patients To avoid possible development of a stye or chalazion To avoid possible eyelash loss To protect patients who are undergoing ocular surgery

67

To protect patients who are undergoing ocular surgery Patients external tissues are an important source of infecting

organisms that adversely affect surgical outcomes Endophthalmitis results from patients own lid and surface flora Surgical outcome adversely affected by inflammation and

dysfunctional tears

Why Is It Important to Treat Posterior Blepharitis?Why Is It Important to Treat Posterior Blepharitis?

Posterior blepharitis is one the most common causes of the following ocular surface symptoms: burning, foreign body sensation and irritation. Potentially enhances ocular surgical outcomes Surgical outcomes may be adversely affected by inflammation

and dysfunctional tears This is particularly important in refractive surgery where achieving

68

This is particularly important in refractive surgery where achieving optimal vision requires a stable tear film

Contributes to contact lens intolerance Prevent conjunctival hyperemia (red eyes) which can be a

significant cosmetic problem for patients Avoid possible eyelash loss Minimize risk for chalazia

Meibomian Gland Meibomian Gland TransilluminationTransillumination

Normal meibomian glands Meibomian gland dysfunction:Extensive acinar dropout

Images from Dry Eye and Ocular Surface Disorders, 2004

TransilluminationTransillumination can reveal can reveal acinaracinar dropout, dropout, meibomianmeibomiancysts (cysts (chalaziachalazia) or scarring ) or scarring (Robin et al, 1985) (Robin et al, 1985)

Diagnostic Procedures NaFl dye: TBUT (tear film stability), corneal

staining (epithelial health), conj. Staining, tear meniscus, lid wiper, corneal valance

Lissamine Green or Rose Bengal gdye: conjunctival staining

Schirmer I or II test or Zone Quick (phenol red thread): tear production

Video Keratoscopy: surface regularity index (SRI)/correlates with visual fluctuation

Tear Meniscus

normal tear prism scant or thin tear prism

EBMDEBMD

13

Corneal Valance(Shahinians Sign)

It is a scalloped horizontal line of tear film thinning seen with fluorescein and cobalt filter in the upper third of the cornea.

Observed in EBMD patients due to minute epithelial Observed in EBMD patients due to minute epithelial irregularities produced by the cysts and excess basement membrane material increasing the rate of contamination of the mucin layer.

Tear Film Break-up Time (TFBUT) Tear film instability is the hallmark of dry eye

Correlates significantly with aqueous and evaporative tear deficiency(Pflugfelder et al, 1998)

TBUT measures tear film quality - Ability to resist thin spots Fluorescein dye introduced from strip or micropipette TBUT = time from completed blink to 1st dry spot (3 repetitions)

Proper patient instruction on procedure. 3 Blinks, look straight ahead. Repeat 3X.

Local alterations of the corneal surface can cause persistent break-up spots

Less is Better Micro-quantities of fluorescein (5l)

yield more precise, reliable TFBUT measurements

Newer Reference Values (n = 200+)

Newer TFBUT Reference ValuesNewer TFBUT Reference Values

Correlating Ocular Discomfort and TFBUT

- In 100s patients, over 70%report ocular awarenessfollowed by discomfort within1 second of TFBUT = NITFBUT Newer Reference Values (n 200 )

Normal > 5 seconds (mean = 7.1 sec)

Dry Eye < 5 seconds (mean = 3.2 sec)

Reference: Lacrimal Gland, Tear Film, and Dry Eye Syndromes 3Edited by D. Sullivan et al., Kluwer Academic/Plenum Publisher 2002

Blink TFBUT BlinkTear ProtectedOcular Surface

UnprotectedOcular Surface

Cycle Repeats

0 1 2 3 4 5 6 7

Time (seconds)

StainingOcularDiscomfortConsequences of an

Unprotected Ocular Surface

TFBUT Patterns:Aqueous Tear Deficiency

Localized circulartear break-up

Diffuse circulartear break-up


TFBUT Patterns:Meibomian Gland Disease

Inferior streaktear break-up

Broad streaktear break-up


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Consequence of Dry Eye = Staining

Damaged corneal cells show up as dry spots during corneal staining

Damaged corneal epithelial cell

(loss of microvilli and glycocalyx)

NaFl Staining in Dry Eye

Lid pattern staining Diffuse staining Meibomian glanddiseaseAqueous tear deficiency


Why is SPK Often Missed?Without Yellow Wratten Filter

Photo courtesy University of Iowa Health Care, January, Photo courtesy University of Iowa Health Care, January, 20052005

With Wratten Filter

Photo courtesy University of Iowa Health Care, January, 2005

Tiffen/Wratten Filter

Adorama42 West 18th StreetNew York, NY 10011800-223-2500

SKU # TF55Y12Tiffen 55mm round/Yellow #12

Rose Bengal Conjunctival Staining in Dry Eye

Classical exposure zone staining

D bl t i l Double triangle pattern characteristic of dry eye

Rose bengal is irritating


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Lissamine Green Stainingin Dry Eye

Lissamine green detects dead or degenerated conjunctival cells Degree of severity increases from left to right pictured above

Exposure zone staining with limbal sparing

Exposure zone staining with limbal staining

Intense diffuse staining of exposure zone,

limbal staining


Delayed clearance correlates well with other measures of dry eye (Afonso et al, 1999; Pflugfelder et al, 1998) Rate of clearance should relate to tear production

5 L of 2% fluorescein instilled; wait 15 min

Tear Turnover in Dry Eye:Fluorescein Clearance

Delayed clearance

Match color of lateral inferior tear meniscus to standard scale

3 is the threshold between normal and symptomatic patients (Afonso et al, 1999)

Other reading methods Insert Schirmer strip, compare to standard colors Fluorometer measures tear concentration directly

Rapid clearance


Impression CytologyTemporal Bulbar Conjunctiva

Normal: Epithelial pattern is regularGoblet cells stain violet

Dry eye: Squamous metaplasiaGoblet cells absent

Detects squamous metaplasia and loss of goblet cells associated with dry eye (Pflugfelder et al, 1990) Goblet cells essential for secretion of soluble mucins into the tear film

An important research toolCytology membrane pressed against conjunctival surface and removedthen stained with periodic acid-Schiff (PAS) or antibodies


Lubricity: an Overlooked Factor in Ocular Health and Comfort

Lubricity is the inverse of the coefficient of friction Two tissues with high lubricity slide smoothly along

one another Lubricity is extremely important in maintaining lid and

ocular health and patient comfortocular health and patient comfortLu

bric

ityLu

bric

ity FrictionFriction

Resistance

Resistance

What is the Lid Wiper?

The lid wiper is that portion of the marginal conjunctiva of the upper

eyelid that wipes the ocular surface during blinking.

The epithelial health of the lid wiper can be determined with a simple graded staining test similar to that used in analyzing the bulbar conjunctiva

Korb, DR, et al. Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 2005 Jan; 31(1):2-8.

Lid Wiper EpitheliopathyLid Wiper Epitheliopathy Characterized by presence of damaged epithelial cells

on lid wiper portion of marginal conjunctivaNaFl, LG or RB can be used to dye the lid wiper Staining graded on scale of 0 to 3, where 0 = no

staining, 3 = heavy staining

1. Korb DR, Herman JP, Greiner JV, et. al: Lid Wiper epitheliopathy and dry eye symptoms. Eye & Contact Lens 31(1): 2-8, 2005.

2. Korb DR, Herman JP, Greiner JV, et. al: Lid Wiper epitheliopathy and dry eye symptoms in contact lens wearers. CLAO J 28: 211-216, 2002.

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Evaluation of the Lubricity of Marketed Dry Eye Products

Performed by Drs. Robert Baier and Ann Meyer, University of Buffalo

Pre-clinical model based on the measurement of friction of tissue on tissue

Measures the coefficient of friction of lubricants on human tissue from stabilized umbilical cord vein graft

Coefficient of Friction/ Comparison of Marketed Ocular Lubricants

*****

##

*p

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How does lacrimal gland disease increase tear osmolarity?

With decreased tear secretion, tear t d Th t iturnover decreases. The tears remain on the eye longer giving evaporation more time to act.

As tear volume declines, but surface area remains constant, evaporation has a greater effect on tear osmolarity.

Differential DiagnosisDifferential DiagnosisDifferential Diagnosis Differential Diagnosis

Differential Diagnoses:other external diseases

Allergic Conjunctivitis Bacterial Conjunctivitis Blepharitis

Contact lens related (mechanical conjunctivitis)

Ocular Rosaceap Viral Conjunctivitis Chlamydia Pemphigoid

Medicamentosa(OTC abuse)

Contact Lens Contact Lens RelatedRelated

Dry Eye IssuesDry Eye Issues

Contact Lenses 101

H2O2O H2O

More hydrophobic less wetting More hydrophilic more wetting

Advancing Contact Angle Receding Contact Angle

Water Model

Contact Lens Care Products, Lens Comfort & the Ocular Surface

Some lens care products produce significant corneal staining.*

Different lens care products possess different wetting capabilities and aredifferent wetting capabilities and are not equally biocompatible with all lens materials.

Studies demonstrate that staining and comfort correlate.

*L. Jones, N. Macdougall, L. Sorbara Asymptomatic Corneal Staining Associated with the Use of Balafilcon Silicone-Hydrogel Contact Lenses Disinfected with a Polyaminopropyl Biguanide-Preserved Care Regimen. Optometry & Visual Science, (2002) 79 (12);753-761

*Young G, Pritchard N, Hunt C, Coleman S. Subjective and Objective Measures of Corneal Staining Related to Multipurpose Care Systems. Contact Lens & Anterior Eye 26 (2003) 3-9

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Therapeutic Approaches Therapeutic Approaches Therapeutic Approaches Therapeutic Approaches p ppp ppp ppp pp

Managing the OSD/Dry Eye Patient

Schedule an OSD evaluation (follow previously discussed history and di ti t ti )diagnostic testing)

Utilize an OSD exam form Code Level 3 E/M or Intermediate

Ophthalmologic Exam (99203/99213/92002/92012)

Delphi Panel 2003 17 international representatives from the U.S. and

Europe Convened in Baltimore to define DTS and develop a

clinically practical scheme for diagnosing and treating dry eye

DEWS 2007 Sponsored by the NEI, published a compendium as a

follow-up to the Delphi Panel findings based on an EBM review of the literature

Beta Panel 2008 ASCRS group recommendations (included loteprednol

and Restasis or Azasite with lid scrubs)

Delphi Panel Consensus for Dry Eye Management

SEVERITY SIGNS AND SYMPTOMS RECOMMENDED TREATMENT

1 Mild to moderate symptoms; no signsMild to moderate conjunctival signs

Patient counseling, preserved tears, environmental management, use of hypoallergenic products, water intake.

2 Moderate to severe symptomsTear film signs

Unpreserved tears, gels, ointments, cyclosporine A, secretagogues, topical

Mild corneal punctate stainingCorneal stainingVisual signs

steroids, nutritional support (flax-seed oil).

3 Severe SymptomsMarked corneal punctate stainingCentral corneal stainingFilamentary keratitis

Tetracyclines, PUNCTAL PLUGS

4 Severe symptomsSevere corneal staining, erosionsConjunctival scarring

Systemic anti-inflammatory therapy, oral cyclosporine, moisture goggles, acetylcysteine, punctal cautery, surgery

Behrens A, et al. (Dysfunctional Tear Film Study Group). Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006 Sep;25(8):900-7.

TREAT

Therapeutic Approaches Stabilize the tear film

(subjective)

Increase lubricity -decrease coefficient of friction TREAT

SUBJECTIVELY

Manage a patients dry eye based on

the medication and dosing that best

fits their particular form of the condition.

Increase aqueous production

Decrease inflammation

Create a more normal tear film environment for epithelial healing

Dry Eye Management

Patient Education Lid Hygiene (treat underlying cause) OTC Therapy

/ O Punctal/Lacrimal Occlusion Nutrition Rx treatment Moisture goggles Surgery

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Patient EducationBefore the diagnostic evaluation.

At the end of the routine exam, explain the tentative diagnosis (of a possible tear film abnormality) to your patient and that you will need to perform specific tests to confirm the diagnosis

Always explain that the testing is medical, not vision y p gcare, and is usually covered by most health insurance plans

After the diagnosis. After making the diagnosis, be specific about the

treatment that you prescribe and prognosis Follow up on the therapy that is prescribed to assess

efficacy

Patient EducationDiscuss/Modify

Influential Factors Environment: humidifier Medications (query OTC use) Fluid consumptionFluid consumption Blink rate Visual tasking: Computer monitor

location (height)

Dry Eye Management

Patient Education Lid Hygiene (treat underlying

cause)OTC Therapy OTC Therapy

Punctal/Lacrimal Occlusion Nutrition Rx treatment Moisture goggles Surgery

Lid HygieneMost important to treat the underlying cause(s) of dry eye (Anterior/Posterior Blepharitis)

Warm Compresses Lid Massage (MG expression in - office) Lid Scrubs (pre-moistened pads or Sterilid) Antibiotic or A-S Ointment or Antibiotic-Steroid gtts for

staphylococcus bacteria/inflammation (Azasite, Erythromycin, Bacitracin, Ciloxan, Tobradex, Zylet)

Oral Tetracycline drugs: Doxycycline 50 mg BID, then 20mg Omega-3 intake Rx pad (pre-printed) with specific instructions Schedule a follow up visit to assess progress and efficacy of

treatment plan (92012/99212)

AzaSite(azithromycin ophthalmic solution) 1%1

AzaSite is indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following microorganisms: CDC coryneform group G*, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and StreptococcusStreptococcus mitis group, and Streptococcus pneumoniae.

*Efficacy for this organism was studied in fewer than 10 infections

1. AzaSite [package insert] Durham, NC: Inspire Pharmaceuticals, Inc. 2007.

Anti-Inflammatory Activity of A ith i & A Sit Azithromycin & AzaSite

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Anti-inflammatory Properties of Azithromycin

Azithromycin has been shown to have significant anti-inflammatory effects as demonstrated by reductions in:1,2,3

inflammatory cell infiltration

edema

mucus hypersecretionmucus hypersecretion

expression of pro-inflammatory cytokines

The anti-inflammatory activity is much higher in cells exposed to bacterial products than in normal cells4

1. Amsden GW. J Antimicrob Chemother. 2005; 55:10-212. Ianaro A, et al. J Pharmacol Exp Ther. 2000; 292(1):156-1633. Shinkai M, et al. Paediatr Respir Rev. 2005;: 6; 227-2354. Glaudue R, et al. Antimicrob Agents Chemother. 1989; 277 - 282

Impact of MMP-9 on Corneal Tissue1

Matrix metalloproteinases (MMPs) coordinate multiple processes in normal, damaged, and diseased corneas.

In normal corneas, MMP-9 is expressed in the epithelium and affects epithelial regeneration and integrity of the basement membrane

Over-expression of MMP-9 involves degradation of epithelial basement membrane and contributes to failure of re-epithelialization following injury

1. Jacot J, et al. Poster Presented at ARVO. Ft. Lauderdale, FL 2008

Suppression of MMP-9 in HCEC by AzaSite

Primary human corneal epithelial cells secrete abundant pro-MMP-91

AzaSite reduced activity of MMP-9 by 33% and MMP-2 by 41% in ocular tissue1

1. Jacot J, et al. Poster Presented at ARVO. Ft. Lauderdale, FL 2008

AzaSite Anti-Inflammatory Conclusions

The macrolide and tetracycline classes of antibiotics have well documented anti-inflammatory effects1,2

Azithromycin specifically has well documented anti-inflammatory effects3,4documented anti inflammatory effects

AzaSite has shown the ability to inhibit production of MMP-9 in ocular tissue5

1. Dougherty JM, et al. The Role of Tetracycline in Chronic Blepharitis. Invest Opthal. Vis Sci. 1991; 32: 2970 2975 2. Pflugfelder SC. Anti-inflammatory Therapy of Dry Eye. The Ocular Surface. 2002; 1: 31-363. Amsden GW. J Antimicrob Chemother. 2005; 55:10-214. Ianaro A, et al. J Pharmacol Exp Ther. 2000; 292(1):156-1635. Jacot J, et al. Poster Presented at ARVO. Ft. Lauderdale, FL 2008

Rapidly improves patient comfort & reduces lid margin and conjunctival hyperemia

Significant anti-inflammatory activity w/o side effects of steroids

AzaSite is disease modifying therapy for Blepharitis

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steroids

Penetrates conjunctiva, cornea and eyelid tissue to achieve effective and sustained levels

Broad spectrum anti-microbial activity

Unique ability to quickly improve meibomian gland secretions

Clinical trials evaluating efficacy of AzaSite for blepharitisClinical trials evaluating efficacy of AzaSite for blepharitis

2 week trial in patients with moderate/severe meibomian gland disease (posterior blepharitis)1 AzaSite provides significant improvement in comfort and reduces lid margin

hyperemia

4 week trial in patients with moderate/severe anterior and posterior (mixed) blepharitis2

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(mixed) blepharitis AzaSite provides significant improvement in comfort and reduces lid margin

and conjunctival hyperemia

4 weeks trial in patients with moderate/severe meibomian gland disease (posterior blepharitis)3 AzaSite rapidly improves patient comfort within one week of beginning therapy

1 Luchs J, Adv Ther, Sept 25 (9):858-870, 20082 Data on file. Inspire Pharmaceuticals, Inc., Study 041-104; accepted for presentation at ASCRS/ARVO 20093 Data on file. Inspire Pharmaceuticals, Inc., Study 041-105; accepted for presentation at ASCRS 2009

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Two week Trial in Posterior Blepharitis: Patient-Rated Efficacy1Two week Trial in Posterior Blepharitis: Patient-Rated Efficacy1

Global Assessment Global Assessment of Efficacy*of Efficacy*

AzaSiteAzaSite in Combination in Combination with Warm Compresseswith Warm Compresses Warm Compresses AloneWarm Compresses Alone

Excellent 25% 0%

Good 50% 18%

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Fair 13% 73%

Poor 13% 9%

Deterioration 0% 0%

75% of patients in the AzaSite group rated the efficacy as excellent or good compared to 18% in the WC alone group (p = 0.024) (n=19)

* per-protocol population

1 Luchs J, Adv Ther, Sept 25 (9):858-870, 2008

Two week Trial in Posterior Blepharitis: Investigator Assessment of Lid Margin HyperemiaTwo week Trial in Posterior Blepharitis: Investigator Assessment of Lid Margin Hyperemia

2

3

4WCAzaSite + WC

p < 0.001

Mea

n Sc

ore

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69% improvement in mean from baseline w/ AzaSite vs. 10% w/ WC alone (n=21)

(0) Normal: no redness (3) Severe: increased vascularity of the eyelid margin(1) Mild: slightly dilated blood vessels (4) Very severe: clearly increased vascularity of the eyelid margin(2) Moderate: more apparent dilation of blood vessels

0

1

Baseline After 2 Weeksof Treatment

M

Luchs J, Adv Ther, Sept 25 (9):858-870, 2008

Four Week Trial in Anterior/Posterior Blepharitis1Four Week Trial in Anterior/Posterior Blepharitis1

AzaSiteAzaSiteVisit 1Visit 1

(Baseline)(Baseline)Visit 2*Visit 2*

(After 4 wks (After 4 wks dosing)dosing)

Visit 3*Visit 3*(2 wks after (2 wks after

dosing stopped)dosing stopped)

Visit 4*Visit 4*(4 wks after (4 wks after

dosing stopped)dosing stopped)Eyelid Margin Hyperemia 2.0 1.3

p

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